Neurometabolic and genetic diseases: a question of screening?


The powerful technologies of tandem mass spectrometry and DNA testing for gene mutations open up a multitude of screening possibilities for neurometabolic and neurodegenerative diseases. The continuing challenge is how best to harness these technologies and link them to public perception and acceptance, clinical imperatives, and financial constraints.1 In a recent consultation exercise, the UK National Screening Committee examined the effectiveness and appropriateness of screening programmes for Canavan disease, familial dysautonomia, and Tay-Sachs disease in Ashkenazi Jewish populations.2,3

The complexity of this question of whether to screen or not to screen is comprehensibly addressed in this consultation document. Some of the criteria are straightforward in that all three are serious, life-limiting conditions that follow an inexorable downward spiral of distressing symptoms. They can be associated with a narrow range of mutations and the overall picture is that the technology is up to the task of screening; it is already in place in some other countries including Australia, Israel, and Canada. However, these diseases are extremely rare in the UK and cultural and financial considerations influence the debate, all of which are aired in the consultation document.

Clinicians working in neurology and neurodisability need to contribute to these debates. Since the introduction in the 1950s of the test for phenylketonuria, the potential and practice in newborn screening for metabolic disease and other inherited conditions has altered beyond recognition. In the late 1960s, bacterial inhibition assay techniques were introduced and over the last 5 years tandem mass spectrometry. Newborn screening for up to 29 core metabolic conditions exists in the United States and up to 10 conditions within parts of Europe. In today’s globalized populations, it is important to avoid assumptions about what screening a patient may have been exposed to.

In the UK there are also debates about national screening programmes for glutaric aciduria type 1 (GA1) which, although rare, is a preventable cause of death and neurodisability.4 This condition presents some interesting questions for these technologies. As an autosomal recessive inherited disorder in which the body is unable to break down completely the amino acids lysine, hydroxylysine, and tryptophan, there is a toxic accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutaryl carnitine due to the defect or deficiency in the enzyme glutaryl-CoA dehydrogenase. This is a particularly intriguing disorder because it can cause early damage to the basal ganglia in particular, leading to movement disorder, decreased muscle tone, and muscle weakness (sometimes confused with cerebral palsy). It can also present with subdural haematoma and retinal haemorrhages, and may need to be considered in the differential diagnosis of inflicted head injury. Tandem mass spectrometry can identify patients with elevated C5 dicarboxylic carnitine (C5DC) in their blood, but the 30% of affected individuals who only excrete minimal or even normal levels of glutaric acid would be missed by this method.5 However, the low excreters are to be found in very specific ethnic groups, so each country needs to know about these populations and interpret whether they have specific DNA mutations which would be amenable to screening.5 Such considerations can influence why some countries have taken up screening for glutaric aciduria type 1 whilst others have not or are in the pilot stages.

Finally, the European Organisation for Rare Diseases (EURORDIS) estimates that there are between 5000 and 7000 distinct rare diseases, but that cumulatively they affect 6% to 8% of the population of the European Union.6 Genetic or heritable conditions are thought to be responsible for 35% of infant deaths and around half of individuals with intellectual disability. This in itself argues for continued engagement of clinicians in these interesting questions of screening, particularly as they become increasingly feasible with the development of advanced technologies.